FU - We wish to examine some of the possible biochemical determinants of the responsiveness of solid tumors to fluorouracil (FU). We have observed long term persistence of high level of FdUMP in the responsive solid L1210 and the rapid disappearance of FdUMP in the unresponsive solid Walker 256 tumors. We will compare alkaline phosphatase levels in these tumors to determine whether resistance to FU relates to destruction of FdUMP by this enzyme, and if tumor responsiveness to FU can be enhanced by inhibiting this enzyme. We also plan to examine the stoichiometry after FU treatment of active thymidylate synthetase, bound thymidylate synthetase, acid soluble FdUMP and dUMP, N5,10-methylenetetrahydrofolate and DNA synthesis as a basis for the antitumor action of FU, and to permit reliable prediction of tissue response to FU. Pt - We shall continue to study the selective protection of host tissues from cis-dichlorodiammine platinum (II) (CDDP) toxicity with mannitol in other tumor bearing species, and the possible protection by mannitol against toxicity of other alkylating agents. To better understand the action of CDDP, we shall determine whether mannitol modifies its disposition and metabolism in the host. DG - We are planning to examine the biochemical effects of 3 deazaguanine (DG) in normal and tumor bearing mice as well as tumor cells to discern the various alterations produced by different concentrations of the drug in relation to growth inhibition. Of particular interest are potential effects on membrane glycoprotein synthesis and surface structure, nucleotide pool sizes and purine biosynthetic enzymes, and the relative rates of DNA, RNA, and protein synthesis. TG - To determine if s6-dG-DNA is the major biochemical lesion responsible for cell death guanine (TG), we wish to evaluate changes in template-enzyme interactions when TG is present in polynucleotides. The extracted DNA containing TG will be examined for specific activity of s6dG in DNA as a function of time and dose; Tm; strand breaks and apurinic region of DNA template activity for DNA and RNA polymerases; and accessibility to enzymes involved in DNA repair.